Cetuximab + Bevacizumab for Brain Tumor

Overseen By Heather McCrea, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Miami

Disqualifiers: Pregnancy, Lactation, Significant medical conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 12 months

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This study assesses the safety and efficacy of repeat monthly dosing of super-selective intra-arterial cerebral infusion (SIACI) of cetuximab and bevacizumab in patients \< 22 years of age.

Will I have to stop taking my current medications?

The trial requires that you stop chemotherapy at least three weeks before starting the treatment. If you are on steroids for brain-related issues, you can continue them as long as the dose is stable or decreasing for at least one week before joining the study. The protocol does not specify other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug combination Cetuximab and Bevacizumab for brain tumors?

Research shows that Cetuximab, when used alone, has been effective against certain brain tumors like glioblastoma multiforme (GBM), and Bevacizumab has shown promising results in improving survival rates in GBM patients. Additionally, a case study reported a complete remission of a relapsed brain tumor with the combination of Cetuximab and Bevacizumab, suggesting potential effectiveness. ^{1 2 3 4 5}

Is the combination of Cetuximab and Bevacizumab safe for humans?

Bevacizumab can cause serious side effects like gastrointestinal perforation (a hole in the stomach or intestines), blood clots, and bleeding in the brain, especially in brain tumor patients. In a study with colorectal cancer patients, the combination of Cetuximab and Bevacizumab was generally well tolerated, with common side effects including rash, low magnesium levels, and fatigue. ^{6 7 8 9 10}

How is the drug combination of Cetuximab and Bevacizumab unique for treating brain tumors?

The combination of Cetuximab and Bevacizumab for brain tumors is unique because Bevacizumab targets and neutralizes VEGF (a protein that promotes blood vessel growth), which is crucial for tumor survival and growth, while Cetuximab is an antibody that targets the epidermal growth factor receptor (EGFR), potentially offering a dual approach to inhibit tumor growth and improve patient outcomes. ^{3 11 12 13 14}

Research Team

Heather McCrea, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for patients under 22 with specific brain tumors that have come back or didn't respond to treatment. They need normal blood counts, liver and kidney function, and can't have had chemotherapy in the last three weeks. They must be able to perform daily activities at a certain level and not planning major surgery soon.

Inclusion Criteria

Must have at least one confirmed and evaluable tumor site

Patients of reproductive age must agree to use a medically effective method of contraception during and for a period of three months after the treatment period. A pregnancy test will be performed on each premenopausal female of childbearing potential immediately prior to entry into the research study

I have a confirmed diagnosis of a specific type of brain tumor.

Exclusion Criteria

Females of childbearing potential and fertile men will be informed as to the potential risk of procreation while participating in this research trial and will be advised that they must use effective contraception during and for a period of three months after the treatment period. If they do not agree, they will be ineligible for the study

I do not have any major health or mental conditions that would make treatment risky for me.

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive monthly super-selective intra-arterial cerebral infusion of Cetuximab and Bevacizumab for up to one year

12 months

Monthly visits for infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month

1 visit (in-person)

Treatment Details

Interventions

• Cetuximab and Bevacizumab

Trial Overview The study tests monthly doses of cetuximab and bevacizumab delivered directly into the artery leading to the brain tumor in young patients. It aims to see how safe this method is and how well it works against aggressive brain tumors.

Participant Groups

Group I: SIACI of cetuximab and bevacizumab Experimental Treatment 1 Intervention

Participants in this group will receive Cetuximab and Bevacizumab infusion into an artery each month for up to approximately one year.

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Findings from Research

In a case study of three patients with recurrent glioblastoma multiforme (GBM) who had already undergone extensive treatment, cetuximab, an EGFR-targeting monoclonal antibody, showed promising responses as a single-agent therapy.

This suggests that targeting the EGFR signaling pathway with cetuximab may provide a new treatment option for patients with recurrent GBM, which typically has poor outcomes with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term responses with cetuximab therapy in glioblastoma multiforme. Belda-Iniesta, C., Carpeño, Jde C., Saenz, EC., et al.[2021]

Cetuximab, an anti-EGFR antibody, significantly increased median survival in mice with EGFR-amplified glioblastoma multiforme (GBM), especially when administered indefinitely, showing a survival increase of at least 900%.

Combining cetuximab with radiation therapy resulted in greater survival benefits than either treatment alone, and preliminary in vitro studies indicated that cetuximab enhanced the cytotoxic effects of chemotherapeutic agents against GBM cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo. Eller, JL., Longo, SL., Kyle, MM., et al.[2019]

Bevacizumab, a monoclonal antibody that targets VEGF, has shown promising results in treating recurrent glioblastoma multiforme (GBM), with notable response rates and progression-free survival at 6 months in various studies.

While early trials indicate that some patients may survive beyond 1 or 2 years on bevacizumab, definitive Phase III trial data are still needed to confirm its efficacy, and it is currently being tested in combination with other treatments for newly diagnosed GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in glioblastoma multiforme. Specenier, P.[2015]

A patient with relapsed glioblastoma achieved a durable complete remission and a 20-month progression-free survival using a combination of cetuximab and bevacizumab in a third-line treatment setting.

The success of this treatment may be attributed to targeting cancer stem cells and enhancing the immune system's ability to attack these cells, suggesting a promising approach for difficult-to-treat gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable complete remission of a brainstem glioma treated with a combination of bevacizumab and cetuximab. Blesa, JM., Mollá, SB., Esparcia, MF., et al.[2021]

Cetuximab was well tolerated in 55 patients with recurrent high-grade glioma, showing limited antitumor activity with only 5.5% achieving a partial response and 29.6% having stable disease.

The median overall survival for patients was 5.0 months, and while a small percentage experienced longer progression-free survival, there was no significant link between treatment response and EGFR gene amplification status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Neyns, B., Sadones, J., Joosens, E., et al.[2022]

In a study of 27 patients with recurrent high-grade gliomas, bevacizumab demonstrated a clinical benefit rate of 59%, with a median progression-free survival (PFS) of 4.3 months and a six-month PFS rate of 43%.

The safety profile included some serious adverse events, with 10 episodes of grade 3/4 side effects, but overall, the efficacy and safety of bevacizumab were found to be comparable to other international studies on similar patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab use for recurrent high-grade glioma at McGill University Hospital. Sahebjam, S., Garoufalis, E., Guiot, MC., et al.[2019]

Bevacizumab, used to treat glioblastoma and other tumors, has a unique toxicity profile that can lead to serious side effects like gastrointestinal perforation and intracranial hemorrhages, particularly in glioblastoma patients.

The study systematically reviewed these adverse events, identifying risk factors and suggesting preventive and therapeutic measures to reduce treatment-related complications, emphasizing the need for careful monitoring in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. Brandes, AA., Bartolotti, M., Tosoni, A., et al.[2022]

In a phase I study involving 41 heavily pretreated patients with metastatic colorectal cancer, the combination of erlotinib, cetuximab, and bevacizumab was well tolerated, with 88% of patients able to handle the full FDA-approved doses without severe side effects.

The treatment showed promising antitumor activity, with 34% of patients achieving stable disease for at least 6 months or a partial response, indicating potential effectiveness in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer. Falchook, GS., Naing, A., Wheler, JJ., et al.[2022]

In a study of 51 patients with non-small cell lung cancer and brain metastases, bevacizumab demonstrated a significant objective response rate of 62.7% and an overall survival of 14 months, indicating its efficacy in this patient population.

Cerebral toxicities occurred in 19.6% of patients, with cardiovascular disease identified as a major risk factor for these complications, highlighting the need for careful patient selection when using bevacizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases. Wang, Z., Yang, JJ., Tu, HY., et al.[2020]

Bevacizumab therapy is associated with several adverse events, the most common being hypertension, which requires regular monitoring and management with antihypertensive medications during treatment.

Close monitoring for other serious complications, such as proteinuria and thromboembolic events, is crucial, as timely management can help prevent severe outcomes and improve patient safety throughout the course of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Understanding and managing the possible adverse effects associated with bevacizumab. Shord, SS., Bressler, LR., Tierney, LA., et al.[2020]

In a retrospective analysis of 28 children with refractory or recurrent brain tumors, bevacizumab was found to have low acute toxicity, with only mild side effects reported, such as hypertension and proteinuria.

While bevacizumab showed some efficacy in reducing tumors in children with low-grade gliomas, it did not demonstrate effectiveness in high-grade gliomas or other tumor types, indicating a need for further research to confirm its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. Couec, ML., André, N., Thebaud, E., et al.[2022]

Bevacizumab, a monoclonal antibody that targets VEGF, has been shown to reduce tumor growth and associated brain swelling in glioblastoma patients, potentially improving their quality of life and survival rates.

Despite its benefits, the review highlights the importance of understanding the potential side effects and complications of bevacizumab, as well as exploring new drug combinations to enhance its efficacy in treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of bevacizumab therapy in the management of glioblastoma. Peak, SJ., Levin, VA.[2021]

In a study of 4191 patients treated with bevacizumab, only 12 (0.3%) experienced intracranial hemorrhage (ICH), indicating that this complication is rare among users of the drug.

The incidence of ICH in patients treated with bevacizumab (3.7%) was similar to the baseline rate (3.6%) in comparable patients not receiving the drug, suggesting that bevacizumab does not significantly increase the risk of ICH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial hemorrhage in patients with cancer treated with bevacizumab: the Memorial Sloan-Kettering experience. Khasraw, M., Holodny, A., Goldlust, SA., et al.[2022]

In a study involving 25 patients with recurrent glioblastoma and anaplastic gliomas, the combination of bevacizumab and hypofractionated stereotactic radiotherapy (HFSRT) was found to be safe and well tolerated, with no cases of radiation necrosis reported.

The treatment showed promising efficacy, with a 50% overall response rate and a median overall survival of 12.5 months, indicating that this regimen could be an effective option for patients with recurrent malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Gutin, PH., Iwamoto, FM., Beal, K., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Long term responses with cetuximab therapy in glioblastoma multiforme. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Bevacizumab in glioblastoma multiforme. [2015]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Durable complete remission of a brainstem glioma treated with a combination of bevacizumab and cetuximab. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Bevacizumab use for recurrent high-grade glioma at McGill University Hospital. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Understanding and managing the possible adverse effects associated with bevacizumab. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. [2022]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Role of bevacizumab therapy in the management of glioblastoma. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Intracranial hemorrhage in patients with cancer treated with bevacizumab: the Memorial Sloan-Kettering experience. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. [2022]